Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control.

TitleTracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control.
Publication TypeJournal Article
Year of Publication2017
AuthorsWilson, MZ, Ravindran, PT, Lim, WA, Toettcher, JE
JournalMol Cell
Volume67
Issue5
Pagination757-769.e5
Date Published2017 Sep 07
ISSN1097-4164
KeywordsAnimals, Computer Simulation, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Feedback, Physiological, Fibroblasts, Gene Expression Profiling, Genes, Immediate-Early, HEK293 Cells, Humans, Immediate-Early Proteins, Light, Mice, Models, Genetic, NIH 3T3 Cells, Optogenetics, Phosphorylation, Platelet-Derived Growth Factor, ras Proteins, RNA Interference, RNA, Messenger, Signal Transduction, Single-Cell Analysis, Time Factors, Transcription, Genetic, Transcriptome, Transfection, Up-Regulation
Abstract

<p>Cell signaling networks coordinate specific patterns of protein expression in response to external cues, yet the logic by which signaling pathway activity determines the eventual abundance of target proteins is complex and poorly understood. Here, we describe an approach for simultaneously controlling the Ras/Erk pathway and monitoring a target gene's transcription and protein accumulation in single live cells. We apply our approach to dissect how Erk activity is decoded by immediate early genes (IEGs). We find that IEG transcription decodes Erk dynamics through a shared band-pass filtering circuit; repeated Erk pulses transcribe IEGs more efficiently than sustained Erk inputs. However, despite highly similar transcriptional responses, each IEG exhibits dramatically different protein-level accumulation, demonstrating a high degree of post-transcriptional regulation by combinations of multiple pathways. Our results demonstrate that the Ras/Erk pathway is decoded by both dynamic filters and logic gates to shape target gene responses in a context-specific manner.</p>

DOI10.1016/j.molcel.2017.07.016
Alternate JournalMol Cell
PubMed ID28826673
PubMed Central IDPMC5591080
Grant List / / Howard Hughes Medical Institute / United States
DP2 EB024247 / EB / NIBIB NIH HHS / United States
P50 GM081879 / GM / NIGMS NIH HHS / United States